Wound contraction is fundamental to the process of wound healing because it reduces the amount of new tissue required to restore organ integrity after tissue damage. This event is known to be mediated by tissue fibroblasts which are responsible for both the deposition of new matrix and its reorganisation. The biological mediators responsible for these processes include cell-derived growth factors and cell adhesion molecules acting through an array of cell membrane receptors (1). The best characterised of these receptors for extracellular matrix proteins is a family of transmembrane heterodimeric molecules termed integrins (2). These receptors comprise an alpha (.alpha.) and beta (.beta.) subunit in noncovalent association and many have been shown to recognize and bind an arginine-glycine-aspartate (referred to as "RGD" using the single letter code) sequence contained within their specific extracellular matrix ligand (3). This supergene family was initially organized into subgroups defined by individual .beta. chains, themselves able to associate with multiple .alpha. chains, and the particular .alpha./.beta. combination determined the ligand specificity. Thus, within the .beta.1 subgroup there are receptors for laminin, collagen and fibronectin with the specific ligand being determined by the associated .alpha. chain (2). More recently, however, it has become clear that the .alpha. chain designated as .alpha.v can associate with multiple .beta.chains, including .beta.1, .beta.3 and .beta.5 (4). Moreover, each of these heterodimeric receptors appears to be able to bind more than one ligand, and at least in the case of .alpha.v.beta.3 this has been attributed to the relatively high affinity of this complex for the RGD sequence (2,5).
Recently, it has been demonstrated (6) that addition of GRGDSP peptide to the platelet integrin glycoprotein (GP)IIb-IIIa (.alpha..sub.IIb .beta.3) conferred new binding specificities to this receptor. This event was monitored by the appearance of new antibody-binding domains termed ligand-induced binding sites (LIBS) some of which were shown to be functionally active in being able to induce fibrin clot retraction.
In work leading up to the present invention, the role of LIBS induction was studied in connection with the reorganisation of the extracellular matrix. The in vitro process of collagen lattice contraction has been considered analogous to the process of wound contraction and has been used as a model to test the effects of putative biological mediators (7). In accordance with the present invention, this model was used to assess the ability of the RGD tripeptide recognition signal to induce functional LIBS and the results obtained impact profoundly on an enhanced procedure for wound healing, and in particular, enhanced intestinal anastomosis.
The development of new surgical techniques, suture materials and stapling instruments has not diminished the ever-present challenge for surgeons insofar as intestinal anastomoses continue to be complicated by leakages even in the best hands. This is particularly true for large bowel anastomoses and a recent large multicentre study reported an average clinical anastomotic breakdown rate of 13% with a mortality rate three times higher for such patients compared with patients free of leakage (8,9). The underlying mechanism responsible is the dramatic decrease in the suture-holding capacity of an anastomosis during the first 3-4 days as a result of changes occurring in the extracellular matrix (10,11,12).
Not surprisingly, efforts to understand matrix metabolism at the anastomotic site have centred on collagen, since it is the predominant extracellular matrix protein. Collagen is in a dynamic state of equilibrium in the body and the normal slow turnover is accelerated at sites of wound repair. The breaking strength of an intestinal anastomosis depends on both the amount and quality of existing collagen through which sutures or staples pass. During the first few days after bowel anastomosis, mature collagen is destroyed thereby decreasing the suture-holding capacity of the bowel ends. It is possible, therefore, that intestinal wound healing could be enhanced through the use of biological response modifiers to increase collagen strength by promoting collagen synthesis and/or altering its structure. One means by which the structure of collagen could be altered at the anastomotic site is via fibroblast-matrix attachments. The importance of fibroblasts in the process of wound healing in general is well recognised and forces generated in fibroblasts organise the surrounding connective tissue matrix resulting in wound contraction.
Hence, the ability to influence fibroblast-mediated re-organisation of existing collagen at the anastomotic site in vivo will serve to enhance its suture-holding capacity by condensing the collagen into a more compact and, thereby, stronger meshwork of interlacing fibrils.
In accordance with the present invention, there is provided a surgical securing means which enhances wound healing by means of inducing fibroblasts to condense the collagen matrix around the wound. The present invention is particularly applicable to enhancing intestinal anastomosis.